rs148293985

Variant names:

• chr11-22279721-A-C
• rs148293985
• NM_213599.3:c.2698A>C

Your query was ambiguous. Multiple possible variants found:

• chr11-22279721-A-C
• chr11-22279721-A-G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_213599.3(ANO5):​c.2698A>C​(p.Met900Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00237 in 1,612,790 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M900T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (9 hom.)
• Consequence: ANO5 NM_213599.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:6
• Conservation: PhyloP100: -0.480
• Publications: 8 publications found

Genes affected

ANO5 (HGNC:27337): (anoctamin 5) This gene encodes a member of the anoctamin family of transmembrane proteins. The encoded protein is likely a calcium activated chloride channel. Mutations in this gene have been associated with gnathodiaphyseal dysplasia. Alternatively spliced transcript variants have been described. [provided by RefSeq, Nov 2009]

ANO5 Gene-Disease associations (from GenCC):

• gnathodiaphyseal dysplasia

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2L

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• Miyoshi muscular dystrophy 3

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0070762336).
• BP6: Variant 11-22279721-A-C is Benign according to our data. Variant chr11-22279721-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195706.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213599.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO5	NM_213599.3	MANE Select	c.2698A>C	p.Met900Leu	missense	Exon 22 of 22	NP_998764.1	Q75V66
	ANO5	NM_001142649.2		c.2695A>C	p.Met899Leu	missense	Exon 22 of 22	NP_001136121.1
	ANO5	NM_001410963.1		c.2656A>C	p.Met886Leu	missense	Exon 21 of 21	NP_001397892.1	A0A804HL91

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO5	ENST00000324559.9	TSL:1 MANE Select	c.2698A>C	p.Met900Leu	missense	Exon 22 of 22	ENSP00000315371.9	Q75V66
	ANO5	ENST00000682341.1		c.2656A>C	p.Met886Leu	missense	Exon 21 of 21	ENSP00000508251.1	A0A804HL91
	ANO5	ENST00000684663.1		c.2653A>C	p.Met885Leu	missense	Exon 21 of 21	ENSP00000508009.1	A0A804HKP2

Frequencies

GnomAD3 genomes AF: 0.00155 AC: 236 AN: 151914 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00290

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00120 AC: 301 AN: 250594 AF XY: 0.00120

Gnomad AFR exome AF: 0.000561

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000464

Gnomad NFE exome AF: 0.00245

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.00246 AC: 3590 AN: 1460876 Hom.: 9 Cov.: 32 AF XY: 0.00231 AC XY: 1680 AN XY: 726694

African (AFR) AF: 0.000269 AC: 9 AN: 33446

American (AMR) AF: 0.0000448 AC: 2 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.000487 AC: 26 AN: 53340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00313 AC: 3474 AN: 1111362

Other (OTH) AF: 0.00126 AC: 76 AN: 60352

GnomAD4 genome AF: 0.00155 AC: 236 AN: 151914 Hom.: 0 Cov.: 32 AF XY: 0.00141 AC XY: 105 AN XY: 74214

African (AFR) AF: 0.000628 AC: 26 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00290 AC: 197 AN: 67842

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.00223 Hom.: 0

Bravo AF: 0.00127

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00268 AC: 23

ExAC AF: 0.00114 AC: 138

EpiCase AF: 0.00251

EpiControl AF: 0.00219

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (4)
-	1	2	not specified (3)
-	-	1	ANO5-related disorder (1)
-	1	-	ANO5-Related Muscle Diseases (1)
-	1	-	Gnathodiaphyseal dysplasia (1)
-	-	1	Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.11
DANN	Benign	0.83
DEOGEN2	Benign	0.046	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.46	N
PhyloP100		-0.48
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.81	N
REVEL	Benign	0.086
Sift	Benign	0.79	T
Sift4G	Benign	0.61	T
Polyphen		0.0	B
Vest4		0.074
MutPred		0.36		Gain of sheet (P = 0.0149)
MVP		0.24
MPC		0.080
ClinPred		0.0052	T
GERP RS		-3.9
Varity_R		0.11
gMVP		0.34
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs148293985; hg19: chr11-22301267;